Alzheimer's disease (AD) and related neurodegenerative diseases are becoming a leading public health challenge. The presence of tau protein-containing neurofibrillary tangles is a major neuropathological hallmark of AD and related tauopathy. Although RNA binding proteins (RBPs) are emerging as critical players in a range of neurodegenerative diseases, little is known about the RBP networks that control the balanced expression of the human tau gene or other AD-associated genes. Based on published studies and preliminary data, we propose to test the hypotheses that the RBP-tau regulatory networks that maintain balanced tau alternative splicing and tau mRNA expression are disrupted in tauopathies, leading to aberrant tau splicing and contributing to pathological tau aggregation and neurodegeneration. We plan to leverage the vast amounts of multi-omics data to construct RBP-tau gene regulatory networks and to use the newly developed hTauKI mouse model together with patient samples and iPSC neurons to validate key players contributing to the pathogenesis of AD and related tauopathies. In Aim 1, we will determine RBP genes and networks that are affected in AD by examining candidate AD-associated RBPs in independent cohorts of patient samples using combined bioinformatics and molecular approaches. In Aim 2, we plan to characterize RBP- tau RNA interactome using human Tau knock-in mice and using iPSC-derived neurons. In Aim 3, we will determine the role of RBP-tau regulatory networks in tau neurotoxicity by dissecting molecular mechanisms of candidate RBPs in regulating tau pre- mRNA splicing and in tau pathogenesis. Our interdisciplinary approach combining systems biology with cutting edge molecular/biochemical assays, using the brand-new human tau knock-in mouse model and iPSC-derived human neurons will, enable us to construct RBP-tau regulatory networks critical for normal brain function. Completion of our proposed study will not only advance the understanding of complex post-transcriptional mechanisms regulating tau expression and provide mechanistic insights into the function of RBP-tau networks, but also lead to information useful for the future development of new diagnostic and therapeutic tools for AD and related dementia.